title: Cortical PKC inhibition promotes axonal regeneration of the corticospinal tract and forelimb functional recovery after cervical dorsal spinal hemisection in adult rats.
abstract: Our previous study shows that conventional protein kinases C (cPKCs) are key signaling mediators that are activated by extracellular inhibitory molecules. Inhibition of cPKC by intrathecal infusion of a cPKC inhibitor, GÖ6976, into the site of dorsal hemisection (DH) induces regeneration of lesioned dorsal column sensory, but not corticospinal tract (CST), axons. Here, we investigated whether a direct cortical delivery of GÖ6976 into the soma of corticospinal neurons promotes regeneration of CST and the recovery of forelimb function in rats with cervical spinal cord injuries. We report that cortical delivery of GÖ6976 reduced injury-induced activation of conventional PKCα and PKCβ1 in CST neurons, promoted regeneration of CST axons through and beyond a cervical DH at C4, formed new synapses on target neurons caudal to the injury, and enhanced forelimb functional recovery in adult rats. When combined with lenti-Chondroitinase ABC treatment, cortical administration of GÖ6976 promoted even greater CST axonal regeneration and recovery of forelimb function. Thus, this study has demonstrated a novel strategy that can promote anatomical regeneration of damaged CST axons and partial recovery of forelimb function. Importantly, such an effect is critically dependent on the efficient blockage of injury-induced PKC activation in the soma of layer V CST neurons.
authors.affiliation: Spinal Cord and Brain Injury Research Group, Stark Neurosciences Research Institute, Department of Neurological Surgery, Indiana University School of Medicine, Indianapolis, IN 46202, USA and.
authors.forename: Xiaofei
authors.initials: X
authors.lastname: Wang
authors.affiliation: Spinal Cord and Brain Injury Research Group, Stark Neurosciences Research Institute, Department of Neurological Surgery, Indiana University School of Medicine, Indianapolis, IN 46202, USA and.
authors.forename: Jianguo
authors.initials: J
authors.lastname: Hu
authors.affiliation: Spinal Cord and Brain Injury Research Group, Stark Neurosciences Research Institute, Department of Neurological Surgery, Indiana University School of Medicine, Indianapolis, IN 46202, USA and.
authors.forename: Yun
authors.initials: Y
authors.lastname: She
authors.affiliation: Department of Physiology Spinal Cord and Brain Injury Research Center, University of Kentucky Chandler Medical Center, Lexington, KY 40636, USA.
authors.forename: George M
authors.initials: GM
authors.lastname: Smith
authors.affiliation: Spinal Cord and Brain Injury Research Group, Stark Neurosciences Research Institute, Department of Neurological Surgery, Indiana University School of Medicine, Indianapolis, IN 46202, USA and.
authors.forename: Xiao-Ming
authors.initials: XM
authors.lastname: Xu
mesh_terms: D000818:Animals; D001710:Biotin / Q000031:analogs & derivatives; D002227:Carbazoles / Q000627:therapeutic use; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000187:drug effects / Q000201:enzymology*; D019765:Chondroitin ABC Lyase / Q000627:therapeutic use; D003911:Dextrans; D004195:Disease Models, Animal; D004622:Embryo, Mammalian; D004791:Enzyme Inhibitors / Q000627:therapeutic use; D005260:Female; D005552:Forelimb / Q000502:physiology*; D007839:Functional Laterality / Q000502:physiology*; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D008297:Male; D009416:Nerve Regeneration / Q000187:drug effects / Q000502:physiology*; D009474:Neurons / Q000166:cytology / Q000187:drug effects / Q000502:physiology; D011247:Pregnancy; D011493:Protein Kinase C / Q000378:metabolism*; D011597:Psychomotor Performance / Q000187:drug effects; D011712:Pyramidal Tracts / Q000187:drug effects / Q000201:enzymology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D020127:Recovery of Function / Q000187:drug effects / Q000502:physiology*; D013119:Spinal Cord Injuries / Q000188:drug therapy / Q000503:physiopathology*
chemical_list: D002227:Carbazoles; D003911:Dextrans; D004791:Enzyme Inhibitors; D005904:Glial Fibrillary Acidic Protein; C076397:biotinylated dextran amine; C081021:Go 6976; D001710:Biotin; D011493:Protein Kinase C; D019765:Chondroitin ABC Lyase
keywords: axonal regeneration; cortical plasticity; corticospinal tract; protein kinase C; spinal cord injury